In the United States, several hundred thousand people experience cardiac arrest each year, with the vast majority dying from this condition. Approximately two-thirds of cardiac arrest victims have previously suffered a myocardial infarction, and the dominant cause of death is a ventricular tachyarrhythmia (VT) originating in the border zone around the infarct scar. Several etiological studies have shown that the changes exhibited by border zone cells are related to cellular electrophysiological function and transcellular communication. These abnormalities slow conduction of the cardiac impulse through this region, creating a substrate for ventricular arrhythmias. This proposal seeks to develop an understanding of the mechanism, efficacy and safety of gene therapy strategies for elimination of post-infarction VT. To achieve this, we will focus on 3 aims: (1) To disrupt reentrant VT circuits by focal and targeted prolongation cellular refractory period with KCNH2-G628S gene transfer to the infarct border zone, (2) to eliminate reentry through the infarct border zone by increasing regional conduction velocity with connexin 43 gene transfer, (3) to assess proarrhythmic risk of KCNH2-G628S or connexin 43 gene therapy for post-infarct VT. Successful completion of these aims will further our understanding of the mechanism responsible for infarct-related VT and possibly allow translation of these findings into novel therapies.